Heteroaromatic amine derivatives

ABSTRACT

The present invention relates to new heteroaromatic amine derivatives of general formula ##STR1## wherein the substituents are defined hereinbelow, which have valuable pharmacological properties, particularly a heart rate lowering activity and a positive inotropic activity.

This is a continuation of application Ser. No. 627,514, now abandoned,filed Dec. 14, 1990, which is a continuation of application Ser. No.455,722, now abandoned filed Dec. 22, 1989.

The present invention relates to new heteroaromatic amine derivatives ofgeneral formula ##STR2## the N-oxides thereof and, if the compoundscontain an optically active carbon atom, the enantiomers and acidaddition salts thereof, particularly, for pharmaceutical use, thephysiologically acceptable acid addition salts thereof with inorganic ororganic acids, processes for preparing them and pharmaceuticalcompositions containing these compounds.

The new compounds have valuable pharmacological properties, particularlya heart rate lowering activity and the effect of reducing the O₂requirements of the heart, as well as a mild hypotensive activity and apositive inotropic activity.

In general formula I above,

n is the number 0 or 1,

A is a methylene, carbonyl or thiocarbonyl group,

B is a methylene, carbonyl or thiocarbonyl group, whilst only one of thegroups A or B may represent a thiocarbonyl group and in this case theother group A or B must represent a methylene group,

E represents a straight-chained alkylene group with 2 to 4 carbon atomsoptionally substituted by an alkyl group with 1 to 3 carbon atoms,

G represents a straight-chained alkylene group with 1 to 6 carbon atomsoptionally substituted by an alkyl group with 1 to 3 carbon atoms,

R₁ and R₂, which may be identical or different, represent hydrogenatoms, alkyl or alkoxy groups each having 1 to 3 carbon atoms in eachalkyl moiety or R₁ and R₂ together represent an alkylenedioxy group with1 or 2 carbon atoms,

R₃ represents a hydrogen atom, an alkenyl group with 3 to 5 carbonatoms, an alkyl or phenylalkyl group, wherein the alkyl moiety maycontain from 1 to 3 carbon atoms, and

Het represents a 5- or 6-membered heteroaromatic ring bound via a carbonor nitrogen atom and containing an oxygen, sulphur or nitrogen atom, twonitrogen atoms or one nitrogen atom and one oxygen or sulphur atom,whilst this ring may additionally be bound via two adjacent carbon atomsto a 1,3-propylene, 1,4-butylene or 1,4-buta-1,3-dienylene group, and inthis case the bonding may be effected via the carbon ring, whilst thecarbon structure of the above-mentioned aromatic and heteroaromaticrings may be mono- or disubstituted by a halogen atom or by an alkyl,hydroxy, alkoxy, phenylalkoxy, phenyl, dimethoxyphenyl, nitro, amino,acetylamino, carbamoylamino, N-alkyl-carbamoylamino, hydroxymethyl,mercapto, alkylmercapto, alkylsulphinyl, alkylsulphonyl,alkylsulphonyloxy, alkylsulphonylamino, alkoxycarbonylmethoxy,carboxymethoxy or alkoxymethyl group or may be substituted by amethylenedioxy or ethylenedioxy group and at the same time any iminogroup present in the above-mentioned heteroaromatic groups may besubstituted by an alkyl, phenylalkyl or phenyl group, and theabove-mentioned alkyl moieties may each contain from 1 to 3 carbonatoms.

As examples of the definitions of the groups given above,

R₁ may represent a hydrogen atom, a methyl, ethyl, n-propyl, isopropyl,methoxy, ethoxy, n-propoxy or isopropoxy group,

R₂ may represent a hydrogen atom, a methyl, ethyl, n-propyl, isopropyl,methoxy, ethoxy, n-propoxy or isopropoxy group or together with R₁ itmay represent a methylenedioxy or ethylenedioxy group,

R₃ may represent a hydrogen atom, a methyl, ethyl, n-propyl, isopropyl,benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl,1-methyl-1-phenylethyl, 3-phenylpropyl, allyl, n-but-2-enyl orn-pent-2-enyl group,

E may represent an ethylene, n-propylene, n-butylene, 1-methylethylene,2-ethyl-ethylene, 1-propylethylene, 1-methyl-n-propylene,2-methyl-n-propylene, 1-ethyl-n-propylene, 3-ethyl-n-propylene,2-propyl-n-propylene or 2-methyl-n-butylene group,

G may represent a methylene, ethylidene, n-propylidene, n-butylidene,2-methyl-propylidene, ethylene, 1-methyl-ethylene, 2-ethyl-ethylene,1-propyl-ethylene, 2-methyl-ethylene, n-propylene, n-butylene,n-pentylene, n-hexylene, 1-methyl-n-propylene, 3-methyl-n-propylene,1-methyl-n-butylene, 1-methyl-n-pentylene, 1-ethyl-n-propylene,2-ethyl-n-propylene or 1-ethyl-n-butylene group and

Het may represent a pyrrol-2-yl, pyrrol-3-yl, N-methyl-pyrrol-2-yl,N-methyl-pyrrol-3-yl, 1,2-dimethyl-pyrrol-3-yl,2,5-dimethyl-pyrrol-3-yl, furan-2-yl, furan-3-yl, 5-methyl-furan-2-yl,2-methyl-furan-3-yl, 5-nitro-furan-2-yl, 5-methoxymethyl-furan-2-yl,benzo[b]furan-2-yl, benzo[b]furan-3-yl, 7-methyl-benzo[b]furan-3-yl,2-methoxy-benzo[b]furan-3-yl, 3-methoxy-benzo[b]furan-2-yl,4-methoxy-benzo[b]furan-3-yl, 5-methoxy-benzo[b]furan-3-yl,6-methoxy-benzo[b]-furan-3-yl, 7-methoxy-benzo[b]furan-3-yl,5-methoxy-3-phenyl-benzo[b]furan-2-yl,3-methyl-5-methoxy-benzo[b]furan-2-yl, thien-2-yl, thien-3-yl,5-methyl-thien-2-yl, 2-methyl-thien-3-yl, 3-methyl-thien-2-yl,2,5-dimethyl-thien-3-yl, 4,5,6,7-tetrahydro-benzo[b]thien-3-yl,4,5,6,7-tetrahydro-benzo[b]thien-2-yl, 5-chloro-thien-2-yl,5-bromo-thien-2-yl, 5-phenyl-thien-2-yl, 2-phenyl-thien-3-yl,benzo[b]thien-2-yl, benzo[b]thien-3-yl, 2,5-dimethyl-benzo[b]thien-3-yl,5-methyl-benzo[b]thien-3-yl, 6-methyl-benzo[b]thien-3-yl,5-chloro-benzo[b]thien-2-yl, 5-bromo-benzo[b]thien-3-yl,6-hydroxy-benzo[b]thien-3-yl, 7-hydroxy-benzo[b]thien-3-yl,5-hydroxy-benzo[b]thien-2-yl, 6-hydroxy-benzo[b]-thien-2-yl,7-hydroxy-benzo[b]thien-2-yl, 3-methoxy-benzo[b]thien-2-yl,4-methoxy-benzo[b]thien-2-yl, 5-methoxy-benzo[b]thien-2-yl,6-methoxy-benzo[b]thien-2-yl, 7-methoxy-benzo[b]thien-2-yl,2-methoxy-benzo[b]thien-3-yl, benzo[b]thien-4-yl, benzo[b]thien-5-yl,benzo[b]thien-6-yl, benzo[b]thien-7-yl, 4-methoxy-benzo[b]thien-3-yl,5-methoxy-benzo[b]thien-3-yl, 6-methoxy-benzo[b]thien-3-yl,7-methoxy-benzo[b]thien-3-yl, 5,6-dimethoxy-benzo[b]-thien-3-yl,5,6-methylenedioxy-benzo[b]thien-3-yl, 6-ethoxy-benzo[b]thien-3-yl,6-n-propoxy-benzo[b]thien-3-yl, 6-isopropoxy-benzo[b]thien-3-yl,6-mercapto-benzo[b]thien-3-yl, 6-methyl-mercapto-benzo[b]thien-3-yl,6-methylsulphinyl-benzo[b]thien-3-yl,6-methylsulphonyl-benzo[b]thien-3-yl,6-methylsulphonyloxy-benzo[b]thien-3-yl,6-methoxycarbonylmethoxy-benzo[b]thien-3-yl,6-ethoxycarbonylmethoxy-benzo[b]thien-3-yl,6-carboxymethoxy-benzo[b]thien-3-yl, 6-amino-benzo[b]thien-3-yl,6-methylamino-benzo[b]thien-3-yl, 6-dimethylamino-benzo[b]thien-3-yl,6-diethylamino-benzo[b]thien-3-yl, 6-acetamino-benzo[b] thien-3-yl,6-methylsulphonylamino-benzo[b]thien-3-yl, pyrazol-1-yl, pyrazol-3-yl,3,5-dimethyl-pyrazol-1-yl, 1,5-dimethyl-pyrazol-3-yl, imidazol-1-yl,imidazol-2-yl, imidazol-4(5)-yl, 1-methyl-imidazol-4-yl,1-benzyl-imidazol-4-yl, 5-nitro-2-methyl-imidazol-1-yl,2-(3,4-dimethoxy-phenyl)-imidazol-4(5)-yl, benzo[d]imidazol-1-yl,2-benzyl-benzo[d]-imidazol-1-yl, benzo[d]imidazol-2-yl, oxazol-4-yl,oxazol-5-yl, isoxazol-3-yl, 3-methyl-isoxazol-5-yl,5-methyl-isoxazol-3-yl, 3,5-dimethyl-isoxazol-4-yl,4-methyl-thiazol-5-yl, benzo[d]oxazol-2-yl, benzo[d]isoxazol-3-yl,benzo[d]thiazol-2-yl, 5-ethoxy-benzo[d]thiazol-2-yl,benzo[d]isothiazol-3-yl, benzo[d]pyrazol-1-yl, benzo[d]pyrazol-3-yl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-3-yl-N-oxide,6-methyl-pyridin-2-yl, 4-nitro-pyridin-2-yl, 4-amino-pyridin-2-yl,4-acetylamino-pyridin-2-yl, 4-carbamoylamino-pyridin-2-yl,4-N-methyl-carbamoylamino-pyridin-2-yl, 2-chloro-pyridin-3-yl,2-chloro-pyridin-4-yl, 6-chloro-pyridin-2-yl,6-hydroxymethyl-pyridin-2-yl, indol-2-yl, indol-3-yl,5-methoxy-indol-3-yl, 5-methyl-indol-3-yl, 7-methyl-indol-3-yl,5-bromo-indol-3-yl, 5-benzyloxy-indol-3-yl, N-methyl-indol-3-yl,quinolin-2-yl, isoquinolin-1-yl, 2-methyl-quinolin-4-yl,7-methyl-quinolin-2-yl, 4-chloro-quinolin-2-yl,6,7-dimethoxy-quinolin-4-yl, 6,7-dimethoxy-isoquinolin-4-yl or6,7-dimethoxy-isoquinolin-4-yl-N-oxide group.

The following compounds which are covered by the scope of the presentinvention may also be mentioned by way of example:

2-[N-methyl-N-(2-(thien-2-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-phthalimide

2-[N-methyl-N-(2-(thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(pyridin-4-yl)-propyl)-3-amino-propyl]-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(pyridin-4-yl)-propyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-isoindole

2-[N-methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(4-(thien-2-yl)-butyl-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2[-N-methyl-N-(2-(benzo[b]furan-2-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(benzo[b]thien-3-yl)-ethyl)-3-amino-propyl-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(indol-3-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(indol-3-yl)-propyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(4-(thien-2-yl)-butyl)-3-amino-propyl]-5,6-dimethoxy-phthalimide

2-[N-methyl-N-(3-(indol-3-yl)-propyl)-3-amino-propyl]-5,6-dimethoxy-phthalimide

2-[N-methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-phthalimide

2-[N-methyl-N-(2-(benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-phthalimide

2-[N-methyl-N-(2-(thien-2-yl)-3-amino-propyl]-5,6-dimethoxy-phthalimide

2-[N-methyl-N-(3-(pyridin-3-yl)-propyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(pyridin-3-yl-N-oxide)-propyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(indol-3-yl)-propyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(pyridin-4-yl)-propyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(pyridin-3-yl)-propyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-((pyridin-3-yl)-methyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-((pyridin-3-yl)-methyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-((pyridin-3-yl)-methyl)-3-amino-propyl]-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-((pyridin-3-yl)-methyl)-3-amino-propyl]-5,6-dimethyl-phthalimide

2-[N-methyl-N-(3-(pyridin-4-yl)-propyl)-3-amino-propyl]-5,6-dimethyl-phthalimide

2-[N-methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-ethyl)-3-aminopropyl]-5,6-dimethyl-phthalimide

2-[N-methyl-N-(2-(pyridin-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-phthalimide

2-[N-methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-phthalimide

2-[N-methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-ethyl)-3-amino-propyl]-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-ethyl)-3-amino-propyl]-6,7-methylenedioxy-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(pyridin-4-yl)-propyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-isoindole

2-[N-methyl-N-(2-(benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1-thioxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(pyridin-2-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(pyridin-4-yl)-propyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(pyridin-3-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(2-methyl-pyridin-6-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(pyridin-2-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(pyridin-3-yl)-propyl)-3-amino-propyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(pyridin-4-yl)-propyl)-3-amino-propyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(pyridin-3-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(pyridin-2-yl)-ethyl)-3-amino-propyl]-6,7-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(pyridin-3-yl)-propyl)-3-amino-propyl]-6,7-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(pyridin-4-yl)-propyl)-3-amino-propyl]-6,7-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(pyridin-3-yl-N-oxide)-propyl)-3-amino-propyl]-6,7-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-((pyridin-3-yl)-methyl-3-amino-propyl]-6,7-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-ethyl)-3-amino-propyl]-6,7-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(pyridin-3-yl)-ethyl)-3-amino-propyl]-6,7-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(pyridin-2-yl)-ethyl)-3-amino-propyl]-6,7-dimethyl-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(pyridin-3-yl)-propyl)-3-amino-propyl]-6,7-dimethyl-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(pyridin-3-yl)-ethyl)-3-amino-propyl]-6,7-dimethyl-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(pyridin-2-yl)-ethyl)-3-amino-propyl]-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(pyridin-3-yl)-propyl)-3-amino-propyl]-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(pyridin-3-yl-N-oxido)-propyl)-3-amino-propyl]-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(pyridin-3-yl)-ethyl)-3-amino-propyl]-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(2-methyl-pyridin-6-yl)-ethyl)-3-amino-propyl]-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(pyridin-2-yl)-ethyl)-3-amino-propyl]-6,7-methylenedioxy-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(pyridin-3-yl)-propyl)-3-amino-propyl]-6,7-methylenedioxy-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(pyridin-3-yl)-ethyl)-3-amino-propyl]-6,7-methylenedioxy-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(pyridin-2-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(pyridin-4-yl)-propyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(pyridin-3-yl-N-oxido)-propyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(pyridin-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(2-methyl-pyridin-6-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-isoindole

2-[N-methyl-N-(2-(pyridin-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-isoindole

2-[N-methyl-N-(2-(pyridin-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-pyridin-3-yl)-propyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(pyridin-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(2-methyl-pyridin-6-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(pyridin-3-yl)-propyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-isoindole

2-[N-methyl-N-(2-(pyridin-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-isoindole

2-[N-methyl-N-(2-(pyridin-2-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(pyridin-3-yl)-propyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(pyridin-4-yl)-propyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(pyridin-3-yl-N-oxido)-propyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-ethyl)-3-aminopropyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(pyridin-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(pyridin-2-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-isoindole

2-[N-methyl-N-(2-(2-methyl-pyridin-6-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-isoindole

2-[N-methyl-N-(2-(benzo[b]thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(4-methoxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-methoxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(6-methoxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-methyl-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-bromo-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(6-methylsulphonyloxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(6-carboxymethoxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-methyl-thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-bromo-thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(2,5-dimethyl-thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-methoxy-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-benzyloxy-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-bromo-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-methyl-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(7-methyl-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(benzo[b]furan-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(benzo[b]furan-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(6-methoxy-benzo[b]furan-3-yl)-ethyl)-3-aminopropyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(7-methoxy-benzo[b]furan-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(furan-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(furan-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-methyl-furan-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(2,5-dimethyl-furan-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(imidazol-4(5)-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(1-methyl-imidazol-4-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(imidazol-1-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(1H-benzo[d]imidazol-1-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(4-methyl-thiazol-5-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(1-methyl-pyrrol-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(benzo[b]thien-2-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(4-methoxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-methoxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(6-methoxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-methyl-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-bromo-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(6-methylsulphonyloxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(6-carboxymethoxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-methyl-thien-2-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-bromo-thien-2-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(2,5-dimethyl-thien-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-methoxy-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-benzyloxy-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-bromo-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-methyl-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(7-methyl-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(benzo[b]furan-2-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(benzo[b]furan-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(6-methoxy-benzo[b]furan-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(7-methoxy-benzo[b]furan-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(furan-2-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-furan-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-methyl-furan-2-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(2,5-dimethyl-furan-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(imidazolyl-4(5))-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(1-methyl-imidazol-4-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(imidazol-1-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(1H-benzo[d]imidazol-1-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(4-methyl-thiazol-5-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(1-methyl-pyrrol-2-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(thien-2-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(indol-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(benzo[b]thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(4-methoxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-methoxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(6-methoxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-methyl-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-bromo-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(6-methylsulphonyloxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(6-carboxymethoxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-methyl-thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-bromo-thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(2,5-dimethyl-thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-methoxy-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-benzyloxy-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-bromo-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-methyl-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(7-methyl-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(benzo[b]furan-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(benzo[b]furan-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(6-methoxy-benzo[b]furan-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(7-methoxy-benzo[b]furan-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(furan-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(furan-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(5-methyl-furan-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(2,5-dimethyl-furan-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(imidazol-4(5)-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(1-methyl-imidazol-4-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(imidazol-1-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(1H-benzo[d]imidazol-1-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(4-methyl-thiazol-5-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(1-methyl-pyrrol-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(benzo[b]thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(4-methoxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(5-methoxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(6-methoxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(5-methyl-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(5-bromo-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(6-methylsulphonyloxy-benzo[b]thien-3-yl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(6-carboxymethoxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(5-methyl-thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(5-bromo-thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(2,5-dimethyl-thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(5-methoxy-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(5-benzyloxy-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(5-bromo-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(5-methyl-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(7-methyl-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(benzo[b]furan-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(6-methoxy-benzo[b]furan-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(7-methoxy-benzo[b]furan-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(furan-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(furan-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(5-methyl-furan-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(2,5-dimethyl-furan-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(imidazol-4(5)-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(1-methyl-imidazol-4-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(imidazol-1-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(1H-benzo[d]imidazol-1-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(4-methyl-thiazol-5-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(1-methyl-pyrrol-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(thien-2-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(indol-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(benzo[b]furan-2-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(benzo[b]thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(4-methoxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(5-methoxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(6-methoxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(5-methyl-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(5-bromo-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(6-methylsulphonyloxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(6-carboxymethoxy-benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(5-methyl-thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(5-bromo-thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(2,5-dimethyl-thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(5-methoxy-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(5-benzyloxy-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(5-bromo-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(5-methyl-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(7-methyl-indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(benzo[b]furan-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(6-methoxy-benzo[b]furan-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(7-methoxy-benzo[b]furan-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(furan-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(furan-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(5-methyl-furan-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(2,5-dimethyl-furan-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(imidazol-4(5)-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(1-methyl-imidazol-4-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(imidazol-1-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(1H-benzo[d]imidazol-1-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(4-methyl-thiazol-5-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(1-methyl-pyrrol-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(benzo[b]furan-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(thien-2-yl)-propyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(4-(thien-2-yl)-butyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(5-(thien-2-yl)-pentyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(thien-3-yl)-propyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(4-(thien-3-yl)-butyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(5-(thien-3-yl)-pentyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(benzo[b]thien-3-yl)-propyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(4-(benzo[b]thien-3-yl)-butyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(furan-2-yl)-propyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(furan-3-yl)-propyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(thien-2-yl)-propyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(4-(thien-2-yl)-butyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(5-(thien-2-yl)-pentyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(thien-3-yl)-propyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(4-(thien-3-yl)-butyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(5-(thien-3-yl)-pentyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(benzo[b]thien-3-yl)-propyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(4-(benzo[b]thien-3-yl)-butyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(furan-2-yl)-propyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(furan-3-yl)-propyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(thien-2-yl)-propyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(4-(thien-2-yl)-butyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(5-(thien-2-yl)-pentyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(thien-3-yl)-propyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(4-(thien-3-yl)-butyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(5-(thien-3-yl)-pentyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(benzo[b]thien-3-yl)-propyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(4-(benzo[b]thien-3-yl)-butyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(furan-2-yl)-propyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(furan-3-yl)-propyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(3-(thien-2-yl)-propyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(4-(thien-2-yl)-butyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-8N-methyl-N-(5-(thien-2-yl)-pentyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(thien-3-yl)-propyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(4-(thien-3-yl)-butyl)-3-amino-propyl]-5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline2-[N-methyl-N-(5-(thien-3-yl)-pentyl)-3-amino-propyl]-5,6-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(benzo[b]thien-3-yl)-propyl)-3-amino-propyl]-5,6-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(4-(benzo[b]thien-3-yl)-butyl)-3-amino-propyl]-5,6-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(furan-2-yl)-propyl)-3-amino-propyl]-5,6-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(furan-3-yl)-propyl)-3-amino-propyl]-5,6-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(thien-2-yl)-propyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(4-(thien-2-yl)-butyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(5-(thien-2-yl)-pentyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(thien-3-yl)-propyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(4-(thien-3-yl)-butyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(5-(thien-3-yl)-pentyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(benzo[b]thien-3-yl)-propyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(4-(benzo[b]thien-3-yl)-butyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(furan-2-yl)-propyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(3-(furan-3-yl)-propyl)-3-amino-propyl]-5,6-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline

2-[N-methyl-N-(2-(thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-thioxo-isoindole

2-[N-methyl-N-(3-(thien-2-yl)-propyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-thioxo-isoindole

2-[N-methyl-N-(4-(thien-2-yl)-butyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-thioxo-isoindole

2-[N-methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-thioxo-isoindole

2[N-methyl-N-(2-(benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-thioxo-isoindole

2-[N-methyl-N-(2-(thien-2-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-thioxo-isoindole

2-[N-methyl-N-(3-(thien-2-yl)-propyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-thioxo-isoindole

2-[N-methyl-N-(4-(thien-2-yl)-butyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-thioxo-isoindole

2-[N-methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-thioxo-isoindole

2-[N-methyl-N-(2-(benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-1-thioxo-isoindole

2-[N-methyl-N-(2-(thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-isoindole

2-[N-methyl-N-(3-(thien-2-yl)-propyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-isoindole

2-[N-methyl-N-(4-(thien-2-yl)-butyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-isoindole

2-[N-methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-isoindole

2-[N-methyl-N-(2-(benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-isoindole

2-[N-methyl-N-(2-(thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-thioxo-isoindole

2-[N-methyl-N-(3-(thien-2-yl)-propyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-thioxo-isoindole

2-[N-methyl-N-(4-(thien-2-yl)-butyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-thioxo-isoindole

2-[N-methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-thioxo-isoindole

2-[N-methyl-N-(2-(benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-thioxo-isoindole

2-[N-methyl-N-(2-(thien-2-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-isoindole

2-[N-methyl-N-(3-(thien-2-yl)-propyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-isoindole

2-[N-methyl-N-(4-thien-2-yl)-butyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-isoindole

2-[N-methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-isoindole

2-[N-methyl-N-(2-(benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-methylenedioxy-1,3-dihydro-isoindole

2-[N-methyl-N-(2-(thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-isoindole

2-[N-methyl-N-(3-(thien-2-yl)-propyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-isoindole

2-[N-methyl-N-(4-(thien-2-yl)-butyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-isoindole

2-[N-methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-isoindole

2-[N-methyl-N-(2-(benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-isoindole

2-[N-ethyl-N-(2-(thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-(2-(thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(thien-2-yl)-ethyl)-3-amino-propyl]-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(thien-2-yl)-methyl)-3-amino-propyl]-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(thien-2-yl)-ethyl)-2-amino-ethyl]-1,3-dihydro-1-oxo-isoindole

2-[N-methyl-N-(2-(thien-2-yl)-ethyl)-4-amino-butyl]-1,3-dihydro-1-oxo-isoindole

However, the preferred compounds of the present invention are thecompounds of general formula ##STR3## wherein n represents the number 0or 1,

A represents a methylene or carbonyl group or, if B represents amethylene group, A may represent a thiocarbonyl group,

B represents a methylene or carbonyl group,

E represents an n-propylene group,

G represents a methylene, ethylene, n-propylene, n-butylene orn-pentylene group,

R₁ and R₂, which may be identical or different, represent hydrogenatoms, methyl or methoxy groups or R₁ and R₂ together represent amethylenedioxy group,

R₃ represents a hydrogen atom, a methyl or allyl group and

Het represents a pyrrol-2-yl, pyrrol-3-yl, N-methyl-pyrrol-2-yl,N-methyl-pyrrol-3-yl, furan-2-yl, furan-3-yl, benzo[b]furan-2-yl,benzo[b]furan-3-yl, 7-methyl-benzo[b]furan-3-yl,6-methoxy-benzo[b]furan-3-yl, 5-methoxy-3-phenyl-benzo[b]furan-2-yl,thien-2-yl, thien-3-yl, 5-methyl-thien-2-yl, 2,5-dimethyl-thien-3-yl,5-bromo-thien-2-yl, benzo[b]thien-2-yl, benzo[b]thien-3-yl,6-hydroxy-benzo[b]thien-3-yl, 6-methoxy-benzo[b]thien-3-yl,5,6-dimethoxy-benzo[b]thien-3-yl, 2,5-dimethyl-benzo[b]thien-3-yl,5-methoxy-benzo[b]thien-2-yl, 6-methoxy-benzo[b]thien-2-yl,6-methylmercapto-benzo[b]thien-3-yl,6-methylsulphinyl-benzo[b]thien-3-yl,6-methylsulphonyl-benzo[b]thien-3-yl,6-methylsulphonyloxy-benzo[b]thien-3-yl,6-ethoxycarbonylmethoxy-benzo[b]thien-3-yl,6-carboxymethoxy-benzo[b]thien-3-yl, 6-dimethylamino-benzo[b]thien-3-yl,6-methylsulphonylamino-benzo[b]thien-3-yl,6-acetamino-benzo[b]thien-3-yl, benzo[b]thien-4-yl, pyrazol-1-yl,pyrazol- 3-yl, 1,5-dimethyl-pyrazol-3-yl, 1-methyl-imidazol-4-yl,2-(3,4-dimethoxy-phenyl)-imidazol-4(5)-yl, benzo[d]imidazol-1-yl,2-benzyl-benzo[d]imidazol-1-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl,3-methyl-isoxazol-5-yl, 4-methyl-thiazol-5-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, pyridin-3-yl-N-oxide, 4-nitro-pyridin-2-yl,4-amino-pyridin-2-yl, 4-acetylamino-pyridin-2-yl,4-carbamoylamino-pyridin-2-yl, 4-N-methylcarbamoylamino-pyridin-2-yl,indol-2-yl, indol-3-yl, 5-methyl-indol-3-yl, 5-methoxy-indol-3-yl,N-methyl-indol-3-yl, 6,7-dimethoxy-quinolin-4-yl,6,7-dimethoxy-isoquinolin-4-yl or 6,7-dimethoxyisoquinolin-4-yl-N-oxidegroup, and the acid addition salts thereof, particularly thephysiologically acceptable acid addition salts thereof with inorganic ororganic acids.

However, particularly preferred compounds of formula Ia above are thosewherein

A, B, E, G and n are defined as hereinbefore,

R₁ and R₂, which may be identical or different, represent methyl ormethoxy groups or R₁ and R₂ represent a methylenedioxy group,

R₃ represents a hydrogen atom or a methyl group and

Het represents a thienyl, furanyl, pyridinyl, pyrid-3-yl-N-oxide,benzo[b]furan-2-yl, benzo[b]furan-3-yl, benzo[b]thien-2-yl,benzo[b]thien-3-yl, indol-3-yl or 6,7-dimethoxy-isoquinolin-4-yl group,and the acid addition salts thereof, particularly the physiologicallyacceptable acid addition salts thereof with inorganic or organic acids.

According to the invention, the new compounds are obtained by thefollowing methods:

a) Reaction of a compound of general formula ##STR4## with a compound ofgeneral formula

    V--G--Het                                                  (III)

wherein R₁, R₂, A, B, E, G, n and Het are defined as hereinbefore, butwherein A or B cannot represent a thiocarbonyl group, one of the groupsU or V represents the R₃ '--NH-- group, wherein R₃ ' represents aprotecting group for an amino group or has the meanings given for R₃hereinbefore, and the other group U or V represents a nucleophilicallyexchangeable group such as a halogen atom or a sulphonyloxy group, e.g.a chlorine, bromine or iodine atom, a methanesulphonyloxy,benzenesulphonyloxy, p-toluenesulphonyloxy or ethoxysulphonyloxy group,and any protecting group used is subsequently split off if necessary.

Examples of protecting groups for an amino or alkylamino group includethe acetyl, benzoyl, ethoxycarbonyl or benzyl groups.

The reaction is conveniently carried out in a solvent or mixture ofsolvents such as acetone, diethylether, methylformamide,dimethylformamide, dimethylsulphoxide, benzene, toluene, chlorobenzene,tetrahydrofuran, benzene/tetrahydrofuran, dioxane or in an excess of thecompounds of general formula II or III used, optionally in the presenceof an acid-binding agent, e.g. an alkoxide such as potassiumtert.-butoxide, an alkali metal hydroxide such as sodium or potassiumhydroxide, an alkali metal carbonate such as potassium carbonate, analkali metal amide such as sodium amide, an alkali metal hydride such assodium hydride, a tertiary organic base such as triethylamine orpyridine, whilst the latter may simultaneously serve as solvent, or areaction accelerator such as potassium iodide, depending on thereactivity of the nucleophilically exchangeable group, conveniently attemperatures between 0° and 150° C., preferably at temperatures between50° and 120° C., e.g. at the boiling temperature of the solvent used.The reaction can, however, be carried out without a solvent. Thereaction is however preferably carried out in the presence of a tertiaryorganic base or an excess of the amines of general formula II or IIIused.

The optional subsequent splitting off of any protecting group used ispreferably carried out hydrolytically in an aqueous solvent, e.g. inwater, isopropanol/water, tetrahydrofuran/water or dioxane/water, in thepresence of an acid such as hydrochloric or sulphuric acid or in thepresence of an alkali metal base such as sodium hydroxide or potassiumhydroxide at temperatures of between 0° and 100° C., preferably at theboiling temperature of the reaction mixture. However, a benzyl group ispreferably split off by hydrogenolysis, e.g. with hydrogen in thepresence of a catalyst such as palladium/charcoal in a solvent such asmethanol, ethanol, ethyl acetate or glacial acetic acid, optionally withthe addition of an acid such as hydrochloric acid at temperatures ofbetween 0° and 50° C., but preferably at ambient temperature, under ahydrogen pressure of from 1 to 7 bar, preferably from 3 to 5 bar.

b) Reaction of a compound of general formula ##STR5## wherein R₁, R₂, A,B and n are as defined hereinbefore, but A or B cannot represent athiocarbonyl group, with a compound of general formula ##STR6## whereinE, G and Het are as defined hereinbefore,

R'₃ represents a protecting group for an amino group or has the meaningsgiven for R₃ hereinbefore and

Z₁ represents a nucleophilically exchangeable group such as a halogenatom or a sulphonyloxy group, e.g. a chlorine, bromine or iodine atom,the methanesulphonyloxy, p-toluenesulphonyloxy or ethoxysulphonyloxygroup, and subsequently if necessary splitting off any protecting groupused.

Examples of protecting groups for an amino or alkylamino group includethe acetyl, benzoyl, ethoxycarbonyl or benzyl group.

The reaction is conveniently carried out in a solvent or mixture ofsolvents such as methylformamide, dimethylformamide, dimethylsulfoxide,benzene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran ordioxane in the presence of an acid binding agent, e.g. an alkoxide suchas potassium tert.butoxide, an alkali metal hydroxide such as sodium orpotassium hydroxide, an alkali metal carbonate such as potassiumcarbonate, an alkali metal amide such as sodium amide or an alkali metalhydride such as sodium hydride, conveniently at temperatures of between0° and 150° C., preferably at temperatures of between 0° and 50° C.

The optional subsequent splitting off of any protecting group used ispreferably carried out hydrolytically in an aqueous solvent, e.g. inwater, isopropanol/water, tetrahydrofuran/water or dioxane/water, in thepresence of an acid such as hydrochloric or sulphuric acid or in thepresence of an alkali metal base such as sodium hydroxide or potassiumhydroxide at temperatures of between 0° and 100° C., preferably at theboiling temperature of the reaction mixture. However, a benzyl group ispreferably split off by hydrogenolysis, e.g. with hydrogen in thepresence of a catalyst such as palladium/charcoal in a solvent such asmethanol, ethanol, ethyl acetate or glacial acetic acid, optionally withthe addition of an acid such as hydrochloric acid at temperatures ofbetween 0° and 50° C., but preferably at ambient temperature, under ahydrogen pressure of from 1 to 7 bar, preferably from 3 to 5 bar.

c) Reductive amination of a compound of general formula ##STR7## in thepresence of a compound of general formula

    V.sub.2 --G--Het                                           (VII)

wherein R₁, R₂, A, B, E, G, Het and n are defined as hereinbefore, oneof the groups U₂ or V₂ represents an R₃ --NH-- group, wherein R₃ isdefined as hereinbefore, and the other group U₂ or V₂ together with ahydrogen atom of the adjacent carbon atom of the group G or E, wherein Eand G are both defined as hereinbefore, represents an oxygen atom.

The reduction is carried out in a suitable solvent such as methanol,ethanol, diethylether, tetrahydrofuran, dioxane, ethyl acetate orethanol/ethyl acetate with a metal hydride such as lithium aluminiumhydride, diborane, sodium cyanoborohydride or borane/dimethylsulphide,but preferably with sodium borohydride, or with hydrogen in the presenceof a hydrogenation catalyst such as platinum, palladium/charcoal orRaney nickel at a hydrogen pressure of 1 to 5 bar or with hydrazine inthe presence of a hydrogenation catalyst such as platinum,palladium/charcoal or Raney nickel, at temperatures of between 0° and50° C., preferably at ambient temperature.

During the reduction with a complex metal hydride such as lithiumaluminium hydride, diborane or borane/dimethylsulphide, a carbonylfunction present in the groups A and/or B may be reduced to form amethylene group or during catalytic hydrogenation any double bondpresent in the group R₃ may be reduced. Furthermore, a thiocarbonylgroup present in the groups A or B or a carbonyl function present in thegroup Het may also be reduced at the same time.

d) Reduction of an acid amide of general formula ##STR8## wherein R₁ toR₃, A, B, Het and n are defined as hereinbefore, one of the groups E₁ orG₁ has the meanings given for E or G hereinbefore and the other group E₁or G₁ also has the meanings given for E or G hereinbefore, but amethylene group adjacent to a nitrogen atom must be replaced by acarbonyl group.

The reduction is preferably carried out in a suitable solvent such asmethanol, ethanol, diethylether or tetrahydrofuran with a suitablereducing agent, e.g. with a metal hydride such as lithium aluminiumhydride, diborane, borane/dimethylsulphide or sodium cyanoborohydride,but preferably with diborane in tetrahydrofuran at between 0° and 40°C., preferably at ambient temperature.

In the reduction with a complex metal hydride such as lithium aluminiumhydride, diborane or borane/dimethyl-sulphide, a carbonyl functionpresent in the groups A and/or B may be reduced to form a methylenegroup. Moreover, a thiocarbonyl group present in the groups A or B or acarbonyl function present in the group Het may also be reduced at thesame time.

e) In order to prepare compounds of general formula I wherein A or Brepresents a thiocarbonyl group: reaction of a compound of generalformula ##STR9## wherein R₁ to R₃, A, B, E, G, Het and n are defined ashereinbefore, but one of the groups A or B must represent a carbonylgroup and the other group A or B must represent a methylene group, witha sulphurizing agent.

The reaction is carried out with a sulphurising agent such as phosphoruspentasulphide or2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulphideconveniently in a solvent such as toluene or xylene at temperatures ofbetween 50° and 150° C., e.g. at the boiling temperature of the reactionmixture.

f) In order to prepare compounds of general formula I wherein A and Beach represent a --CH₂ -- group: reduction of a compound of generalformula ##STR10## wherein R₁ to R₃, E, G, Het and n are defined ashereinbefore, one of the radicals A' or B' represents a carbonyl orthiocarbonyl group and the other of the radicals A' or B' represents amethylene, carbonyl or thiocarbonyl group.

The reduction is preferably carried out with a metal hydride such aslithium aluminium hydride or diborane or with a complex of borane and athioether, e.g. with borane-dimethylsulphide complex, in a suitablesolvent such as diethylether or tetrahydrofuran at temperatures ofbetween 0° and 50° C., but preferably at temperatures of between 10° and25° C. Moreover, B or a carbonyl function present in the group Het maybe reduced at the same time.

g) In order to prepare compounds of general formula I wherein Arepresents a methylene group: reduction of a compound of general formula##STR11## wherein R₁ to R₃, A, B, E, G, Het and n are defined ashereinbefore.

The reduction is preferably carried out in a suitable solvent such asglacial acetic acid, water, ethanol or water/glacial acetic acid,conveniently with nascent hydrogen, e.g. in the presence of zinc/glacialacetic acid, tin/hydrochloric acid or tin(II) chloride/hydrochloricacid, or with catalytically activated hydrogen at temperatures ofbetween 0° and 150° C., preferably at temperatures of between 20° and125° C. Any double bond present in the group R₃ or any nitro groupcontained in the group Het may also be reduced at the same time.

If they have at least one chiral centre, the compounds of generalformula I obtained can be resolved by conventional methods into theirdiastereomers, for example by column chromatography, and into theirenantiomers, for example by column chromatography on a chiral phase orby crystallization with optically active acids, e.g. with D- orL-monomethyltartaric acid, D- or L-diacetyltartaric acid, D- orL-tartaric acid, D- or L-lactic acid or D- or L-camphoric acid.

The compounds of general formula I obtained may also be converted intothe acid addition salts thereof, particularly for pharmaceutical useinto the physiologically acceptable acid addition salts thereof withinorganic or organic acids. Suitable acids include, for example,hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, lactic,citric, tartaric, succinic, maleic and fumaric acids.

The compounds of general formulae II to XI used as starting materialsare known from the literature in some cases or may be obtained usingmethods known per se.

Thus, for example, a compound of general formula ##STR12## (wherein R₁,R₂ and n are defined as hereinbefore, A represents a carbonyl group andB represents a methylene group) used as starting material may beprepared by cyclizing a corresponding compound of general formula##STR13## with polyphosphoric acid or a compound of general formula IVwherein R₁, R₂ and n are defined as hereinbefore, A and B each representa CO group, may be prepared by cyclizing a corresponding diamide. Acompound of general formula IV thus obtained may subsequently beconverted into a corresponding methylene compound by reduction.

The compounds of general formulae II, VI and VIII-XI used as startingmaterials are obtained by reacting a compound of general formula IV witha corresponding halogen compound or a corresponding dihalogen compound,optionally followed by reaction with a corresponding amine.

As already mentioned hereinbefore, the new compounds of general formulaI and the physiologically acceptable acid addition salts thereof withinorganic or organic acids have valuable pharmacological properties,particularly a lowering effect on heart rate and the effect of reducingthe O₂ requirement of the heart, together with a mild hypotensiveactivity and a positive inotropic activity.

For example, the following compounds:

A=2-[N-methyl-N-(2-(benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolinehydrochloride,

B=2-[N-methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindoledihydrochloride and

C=2-[N-methyl-N-(2-(benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindoledihydrochloride were tested for their biological properties as follows:

Determination of the Positive Inotropic and Heart Rate Lowering Activityon Isolated Guinea-Pig Auricles

The positive inotropic activity was determined as the effect on thecontractility of isolated guinea-pig auricles. Freshly preparedguinea-pig auricles were transferred into a 65 ml organ bath filled withKrebs-Henseleit solution (1.8 mM Ca⁺⁺) at 37° C. Carbogen (95% oxygenand 5% carbon dioxide) was bubbled through the bath. The auricles werestimulated electrically at a rate of 1 Hz; their pre-extension was 10mN. The contractions were recorded isometrically on a Grass polygraph.After an equilibration period of 60 minutes the test substances wereadministered so as to obtain a final concentration of 10⁻⁵ M.

The effect on heart rate was determined on spontaneously beatingguinea-pig auricles in a test arrangement otherwise identical to thatdescribed above.

The following Table contains the averages of two measurements in eachcase:

    ______________________________________                                                    Increase in force of                                                                        Change in heart                                     Substance   contractions in %                                                                           rate in %                                           ______________________________________                                        A           +54           -21                                                 B           +127          -17                                                 C           +61           -41                                                 ______________________________________                                    

In view of their pharmacological properties, the compounds preparedaccording to the invention are suitable for the treatment of cardiacinsufficiency and for the prevention and treatment of ischaemic heartdisease.

The dosage required to achieve this effect is conveniently from 0.2 to 5mg/kg of body weight, preferably from 0.5 to 2 mg/kg of body weight,once or twice a day. The compounds of general formula I and thephysiologically acceptable acid addition salts thereof with inorganic ororganic acids produced according to the invention may be incorporated,optionally together with other active substances, with one or more inertconventional carriers and/or diluents, e.g. with corn starch, lactose,glucose, microcrystalline cellulose, magnesium stearate,polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol,water/glycerol, water/sorbitol, water/polyethyleneglycol,propyleneglycol, carboxymethylcellulose or fatty substances such as hardfat or suitable mixtures thereof, to produce conventional galenicpreparations such as tablets, coated tablets, capsules, powders,suspensions, drops, ampoules, syrups or suppositories.

The following Examples are intended to illustrate the invention:

EXAMPLE 12-[N-Methyl-N-(2-(thien-2-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolinehydrochloride

0.85 g (3.0 mmol) of2-(N-methyl-3-amino-propyl)-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline,0.60 g (3.1 mmol) of 2-(2-bromo-ethyl)-thiophene and 5 ml oftriethylamine are dissolved in 10 ml of dry dimethylformamide and heatedto 100° C. for 4 hours. The reaction mixture is evaporated down in vacuoand the residue is dissolved in a mixture of 2 molar sodium hydroxidesolution and methylene chloride. The organic phase is separated off,washed with saturated saline solution, dried over sodium sulphate andevaporated down in vacuo. The crude product is purified by columnchromatography (adsorption agent: silica gel, eluant: methylenechloride/methanol=10/1). The hydrochloride is precipitated from asolution in methanol with ethereal hydrochloric acid and thencrystallized from acetone.

Yield: 0.40 g (31% of theory), Melting point: 150°-151° C.; Calculated:C, 59.35; H, 6.88; N, 6.59; Cl, 8.34; S, 7.54. Found: C, 59.40; H, 6.73;N, 6.29; Cl, 8.11; S, 7.59. R_(f) value (base): 0.42 (silica gel,methylene chloride in an NH₃ atmosphere).

EXAMPLE 22-[N-Methyl-N-(2-(indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-phthalimide

1.15 g (3.5 mmol) of 2-(3-bromo-propyl)-5,6-dimethoxy-phthalimide aredissolved in 15 ml of absolute dimethylformamide with gentle heating.After the addition of 0.61 g (3.5 mmol) of3-(2-methylamino-ethyl)-indole and 15 ml of triethylamine the mixture isrefluxed for 8 hours. The reaction mixture is evaporated to dryness invacuo and distributed between 8% sodium hydroxide and methylenechloride. The organic phase is washed three times with 10 ml of water,separated off, dried with sodium sulphate and evaporated down. Afterpurification over a silica gel column using methylene chloride/methanolas eluant, 0.9 g of a yellow oil are obtained.

Yield: 0.90 g (61% of theory), Calculated: C, 68.39; H, 6.46; N, 9.97.Found: C, 68.28; H, 6.50; N, 9.91. R_(f) value: 0.47 (silica gel,methylene chloride/methanol=9/1).

EXAMPLE 32-[N-Methyl-N-(2-(thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindolehydrochloride

1.5 g (3.9 mmol) of2-[N-methyl-N-(2-(thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-phthalimideand 1.5 g (23 mmol) of zinc powder are refluxed for 1.5 hours in 15 mlof glacial acetic acid. The mixture is filtered whilst still hot toremove the insoluble matter and the residue is extracted twice, eachtime with 8 ml of hot glacial acetic acid. The collected acetic acidphases are evaporated down in vacuo and the residue is distributed in 8%sodium hydroxide solution and methylene chloride. The organic phase iswashed with water, separated off, dried over sodium sulphate andevaporated down in vacuo. The purification of the crude product over asilica gel column using methylene chloride/methanol as eluant yields 1.1g (75% of theory) of a yellow oil. It is dissolved in a little absolutemethanol and the hydrochloride is precipitated with etherealhydrochloric acid.

Yield: 1.0 g (62% of theory), Melting point: 211°-212° C.; Calculated:C, 58.45; H, 6.62; N, 6.82; Cl, 8.63; S, 7.80. Found: C, 58.68; H, 6.80;N, 7.00; Cl, 8.84; S, 7.59. R_(f) value (base): 0.55 (silica gel,methylene chloride/methanol=9/1).

EXAMPLE 42-[N-Methyl-N-(3-(pyrid-4-yl)-propyl)-3-amino-propyl]-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinolinedihydrochloride

1.3 g (5 mmol) of2-(2-formyl-ethyl)-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinolineand 0.75 g (5 mmol) of 4-(3-methylamino-propyl)pyridine are hydrogenatedin 50 ml of ethanol in the presence of 0.2 g of 10% palladium onactivated charcoal at 70° C. and 5 bar until the calculated quantity ofhydrogen has been absorbed. The catalyst is filtered off and thefiltrate is evaporated to dryness in vacuo. The dihydrochloride isprecipitated with ethereal hydrochloric acid from a solution in acetoneand is then recrystallized from acetone/ether.

Yield: 1.7 g (74% of theory), Melting point: 86°-94° C.; Calculated: C,58.15; H, 6.43; N, 9.24; Cl, 15.60. Found: C, 57.91; H, 6.31; N, 9.15;Cl, 15.36.

The reduction may also be carried out with sodium borohydride in ethanolat ambient temperature or at boiling point.

EXAMPLE 52-[N-Methyl-N-(3-(pyrid-4-yl)-propyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-isoindoledihydrochloride

A mixture of 2.0 g (5.7 mmol) of2-[N-methyl-N-(3-pyrid-4-yl)-propyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindoleand 0.43 g (11.4 mmol) of lithium aluminium hydride in 45 ml of absolutetetrahydrofuran is refluxed for 1 hour. After cooling, the mixture isdecomposed with 0.57 ml of water, 0.57 ml of 10% sodium hydroxidesolution and 1.71 ml of water, then suction filtered and the filtrate isevaporated down in vacuo. The residue obtained is purified over 180 g ofaluminium oxide (neutral, activity II-III) with methylene chloride andthen with increasing amounts of ethanol (up to 3%). The dihydrochlorideis precipitated with ethereal hydrochloric acid from a solution inacetone.

Yield: 1.85 g (80% of theory), Melting point: 239°-241° C.; Calculated:C, 64.37; H, 8.10; N, 10.23; Cl, 17.27. Found: C, 64.20; H, 8.37; N,10.07; Cl, 17.36.

EXAMPLE 62-[N-Methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolinedihydrochloride a)2-[N-Methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-acetyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolinehemihydrate

3.2 g (20 mmol) of N,N'-carbonyl-diimidazole are added to a solution of4.9 g (17 mmol) of 6,7-dimethoxy-isoquinolin-4-yl-acetic acid in 100 mlof dimethylformamide. After about 30 minutes 4.8 g (17 mmol) of2-(3-methylamino-propyl)-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolineare added and the mixture is stirred for 2 hours at ambient temperature.The solvent is evaporated off in vacuo and the residue remaining isdissolved in a mixture of 2 molar sodium hydroxide solution andmethylene chloride. The organic phase is washed with water, dried overmagnesium sulphate and evaporated down in vacuo.

Yield: 5.3 g (63% of theory), Melting point: 80°-85° C.; Calculated: C,65.10; H, 6.63; N, 8.13. Found: C, 64.90; H, 6.63; N, 8.15.

b)2-[N-Methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolinedihydrochloride

To a solution of 4.1 g (8 mmol) of2-[N-methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-acetyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolinehemihydrate in 250 ml of tetrahydrofuran are added 12 ml of 1 molarborane-tetrahydrofuran complex in tetrahydrofuran and whilst the mixtureis stirred at ambient temperature 1.5 ml (12 mmol) of borontrifluoride-diethyletherate complex are added dropwise. After 3 hours'reaction, 15 ml of 6 molar hydrochloric acid are added dropwise, themixture is refluxed for 0.5 hours and the solvent is then evaporated offin vacuo. The aqueous portion remaining is made alkaline with 2 molarsodium hydroxide solution and then extracted with methylene chloride.The organic phase is washed with water, dried over sodium sulphate,evaporated down in vacuo and purified over a silica gel column(0.063-0.2 mm) with methylene chloride and then with increasing amountsof ethanol (up to 5%). The dihydrochloride is precipitated with etherealhydrochloric acid from a solution in acetone and is then recrystallizedfrom acetone.

Yield: 0.45 g (10% of theory), Melting point: 158°-169° C. Calculated:C, 59.36; H, 6.58; N, 7.42; Cl, 12.52. Found: C, 59.20; H, 6.60; N,7.27; Cl, 12.22.

The reduction may also be carried out with lithium aluminium hydride inether or tetrahydrofuran at reflux temperature.

EXAMPLE 72-[N-Methyl-N-(4-(thien-2-yl)-butyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline-hydrochloride

Prepared from2-(N-methyl-3-amino-propyl)-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolineand 2-(4-bromo-butyl)-thiophene analogously to Example 1.

Yield: 64% of theory, Melting point: 115°-120° C.; Calculated: C, 60.98;H, 7.34; N, 6.18; Cl, 7.83; S 7.08. Found: C, 60.70; H, 7.44; N, 5.96;Cl, 8.15; 7.03. R_(f) value: 0.29 (silica gel, methylene chloride in anNH₃ atmosphere).

EXAMPLE 82-[N-Methyl-N-(2-(benzo[b]furan-2-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolinehydrochloride

Prepared from2-(N-methyl-3-amino-propyl)-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolineand 2-(2-chloro-ethyl)-benzo[b]furan analogously to Example 1.

Yield: 24% of theory, Melting point: 180°-184° C.; Calculated: C, 65.42;H, 6.81; N, 6.10; Cl, 7.72. Found: C, 65.40; H, 6.80; N, 5.92; Cl, 7.98.

EXAMPLE 92-[N-Methyl-N-(2-(benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolinehydrochloride

Prepared from2-(N-methyl-3-amino-propyl)-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolineand 3-(2-methylsulphonyloxyethyl)-benzo[b]thiophene analogously toExample 1.

Yield: 38% of theory, Calculated: C, 63.21; H, 6.58; N, 5.90; Cl, 7.46;S, 6.75. Found: C, 63.10; H, 6.47; N, 5.86; Cl, 7.55; S, 6.88. R_(f)value: 0.37 (silica gel, methylene chloride in an NH₃ atmosphere).

EXAMPLE 102-[N-Methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolinehydrochloride

Prepared from2-(N-methyl-3-amino-propyl)-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolineand 3-(2-bromo-ethyl)-thiophene analogously to Example 1.

Yield: 34% of theory, Calculated: C, 59.35; H, 6.88; N, 6.59; Cl, 8.34;S, 7.54. Found: C, 59.47; H, 6.77; N, 6.57; Cl, 8.59; S, 7.37. R_(f)value: 0.34 (silica gel, methylene chloride in an NH₃ atmosphere).

EXAMPLE 112-[N-Methyl-N-(2-(indol-3-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline-hydrochloride

Prepared from2-(N-methyl-3-amino-propyl)-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolineand 3-(2-chloro-ethyl)-indole analogously to Example 1.

Yield: 32% of theory, Calculated: C, 65.56; H, 7.04; N, 9.17; Cl, 7.74.Found: C, 65.38; H, 6.93; N, 9.01; Cl, 7.97. R_(f) value: 0.45 (silicagel, methylene chloride/methanol=10/1 in an NH₃ atmosphere).

EXAMPLE 122-[N-Methyl-N-(3-(indol-3-yl)-propyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline-hydrochloride

Prepared from2-(N-methyl-3-amino-propyl)-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolineand 3-(3-methylsulphonyloxypropyl)-indole analogously to Example 1.

Yield: 38% of theory, Calculated: C, 66.16; H, 7.26; N, 8.90; Cl, 7.51.Found: C, 65.98; H, 7.56; N, 8.85; Cl, 7.54. R_(f) value: 0.34 (silicagel, methylene chloride/methanol=10/1 in an NH₃ atmosphere).

EXAMPLE 132-[N-Methyl-N-(4-(thien-2-yl)-butyl)-3-amino-propyl]-5,6-dimethoxy-phthalimide

Prepared from 2-(3-methylamino-propyl)-5,6-dimethoxy-phthalimide and2-(4-bromo-butyl)-thiophene analogously to Example 1.

Yield: 80% of theory, Calculated: C, 63.44; H, 6.78; N, 6.73; S, 7.70.Found: C, 63.50; H, 6.71; N, 6.75; S, 7.90. R_(f) value: 0.57 (silicagel, methylene chloride/methanol=9/1).

EXAMPLE 142-[N-Methyl-N-(3-(indol-3-yl)-propyl)-3-amino-propyl]-5,6-dimethoxy-phthalimide

Prepared from 2-(3-methylamino-propyl)-5,6-dimethoxy-phthalimide and3-(3-methylsulphonyloxy-propyl)-indole analogously to Example 1.

Yield: 51% of theory, Calculated: C, 68.95; H, 6.71; N, 9.65. Found: C,69.20; H, 6.78; N, 9.60. R_(f) value: 0.36 (silica gel, methylenechloride/methanol=9/1).

EXAMPLE 152-[N-Methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-phthalimide

Prepared from 2-(3-methylamino-propyl)-5,6-dimethoxy-phthalimide and3-(2-bromo-ethyl)-thiophene analogously to Example 1.

Yield: 73% of theory, Calculated: C, 61.84; H, 6.23; N, 7.21; S, 8.25.Found: C, 61.64; H, 6.28; N, 7.19; S, 8.09. R_(f) value: 0.48 (silicagel, methylene chloride/methanol=9/1).

EXAMPLE 162-[N-Methyl-N-(2-(benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-phthalimide

Prepared from 2-(3-methylamino-propyl)-5,6-dimethoxy-phthalimide and3-(2-methylsulphonyloxy-ethyl)-benzo[b]thiophene analogously to Example1.

Yield: 41% of theory, Calculated: C, 65.73; H, 5.98; N, 6.39; S, 7.31.Found: C, 65.78; H, 5.80; N, 6.19; S, 7.42. R_(f) value: 0.61 (silicagel, methylene chloride/methanol=9/1).

EXAMPLE 172-[N-Methyl-N-(2-(thien-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-phthalimide

Prepared from 2-(3-methylamino-propyl)-5,6-dimethoxy-phthalimide and3-(2-bromo-ethyl)-thiophene analogously to Example 1.

Yield: 44% of theory, Calculated: C, 61.84; H, 6.23; N, 7.21; S, 8.25.Found: C, 61.59; H, 6.20; N, 7.02; S, 8.42. R_(f) value: 0.24 (silicagel, methylene chloride/methanol=9/1).

EXAMPLE 182-[N-Methyl-N-(3-(pyridin-3-yl)-propyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolinedihydrochloride-monohydrate

Prepared from2-(3-methylamino-propyl)-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolineand 3-(3-chloro-propyl)-pyridine analogously to Example 1.

Yield: 31% of theory, Calculated: C, 56.55; H, 7.22; N, 8.60; Cl, 14.51.Found: C, 56.53; H, 7.49; N, 8.45; Cl, 14.71. R_(f) value: 0.20 (silicagel, ethyl acetate/ethanol/ammonia=80/40/2).

EXAMPLE 192-[N-Methyl-N-(3-(pyridin-3-yl-N-oxide)-propyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolinedihydrochloride

Prepared from2-(3-methylamino-propyl)-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolineand 3-(3-chloro-propyl)-pyridine-N-oxide analogously to Example 1.

Yield: 33% of theory, Calculated: C, 57.02; H, 6.45; N, 8.67; Cl, 14.63.Found: C, 57.07; H, 6.23; N, 8.44; Cl, 14.57. R_(f) value: 0.35 (silicagel, ethyl acetate/ethanol/ammonia=50/45/5).

EXAMPLE 202-[N-Methyl-N-(2-(indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindolehydrochloride

Prepared from2-[N-methyl-N-(2-(indol-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-phthalimideanalogously to Example 3.

Yield: 25% of theory, Calculated: C, 64.93; H, 6.81; N, 9.47; Cl, 7.99.Found: C, 64.80; H, 6.81; N, 9.41; Cl, 8.03. R_(f) value: 0.29 (silicagel, methylene chloride/methanol=9/1).

EXAMPLE 212-[N-Methyl-N-(3-(indol-3-yl)-propyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindolehydrochloride

Prepared from2-[N-methyl-N-(3-(indol-3-yl)-propyl)-3-amino-propyl]-5,6-dimethoxy-phthalimideanalogously to Example 3.

Yield: 24% of theory, Calculated: C, 65.56; H, 7.04; N, 9.18; Cl, 7.74.Found: C, 65.41; H, 7.24; N, 8.86; Cl, 7.91. R_(f) value: 0.36 (silicagel, methylene chloride/methanol=6/4).

EXAMPLE 222-[N-Methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindoledihydrochloride

Prepared from2-[N-methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-phthalimideanalogously to Example 3.

Yield: 70% of theory, Melting point: 187°-188° C.; Calculated: C, 53.69;H, 6.31; N, 6.30; Cl, 15.85; S, 7.16. Found: C, 53.54; H, 6.49; N, 6.48;Cl, 15.78; S, 7.17. R_(f) value: 0.43 (silica gel, methylenechloride/methanol=9/1).

EXAMPLE 232-[N-Methyl-N-(2-(benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindoledihydrochloride

Prepared from2-[N-methyl-N-(2-(benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-phthalimideanalogously to Example 3.

Yield: 63% of theory, Calculated: C, 57.94; H, 6.08; N, 5.63; Cl, 14.25;S, 6.44. Found: C, 58.19; H, 6.25; N, 5.82; Cl, 14.32; S, 6.26. R_(f)value: 0.43 (silica gel, methylene chloride/methanol=9/1).

EXAMPLE 242-[N-Methyl-N-(3-(pyridin-4-yl)-propyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

Prepared from2-[N-methyl-N-(3-(pyridin-4-yl)-propyl)-3-amino-propyl]-5,6-dimethyl-phthalimideanalogously to Example 3.

Yield: 80% of theory, Melting point: 82°-84° C.; Calculated: C, 75.17;H, 8.32; N, 11.95. Found: C, 74.98; H, 8.39; N, 11.76.

EXAMPLE 252-[N-Methyl-N-(3-(pyridin-3-yl)-propyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindolehydrochloride

Prepared from2-[N-methyl-N-(3-(pyridin-3-yl)-propyl)-3-amino-propyl]-5,6-dimethoxy-phthalimideanalogously to Example 3.

Yield: 60% of theory, Melting point: 180°-182° C. Calculated: C, 62.91;H, 7.20; N, 10.00; Cl, 8.44. Found: C, 62.75; H, 7.09; N, 9.85; Cl,8.14.

EXAMPLE 262-[N-Methyl-N-((pyridin-3-yl)-methyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindoledihydrochloride

Prepared from2-[N-methyl-N-((pyridin-3-yl)-methyl)-3-amino-propyl]-5,6-dimethoxy-phthalimideanalogously to Example 3.

Yield: 72% of theory, Calculated: C, 56.07; H, 6.35; N, 9.81; Cl, 16.55.Found: C, 56.16; H, 6.38; N, 9.85; Cl, 16.44. R_(f) value: 0.35 (silicagel, ethyl acetate/ethanol/ammonia=90/10/1).

EXAMPLE 272-[N-Methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindolehydrochloride

Prepared from2-[N-methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-phthalimideanalogously to Example 3.

Yield: 90% of theory, Melting point: 202°-204° C.; Calculated: C, 62.84;H, 6.64; N, 8.14; Cl, 6.87. Found: C, 62.61; H, 6.78; N, 7.95; Cl, 6.59.R_(f) value: 0.50 (silica gel, ethyl acetate/ethanol/ammonia=50/45/5).

EXAMPLE 282-[N-Methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindoledihydrochloride-monohydrate

Prepared from2-[N-methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-phthalimideanalogously to Example 3.

Yield: 81% of theory, Melting point: 227°-229° C.; Calculated: C, 60.22;H, 6.92; N, 7.80; Cl, 13.16. Found: C, 60.40; H, 7.03; N, 8.05; Cl,13.08.

EXAMPLE 292-[N-Methyl-N-((pyridin-3-yl)-methyl)-3-amino-propyl]-5,6-dimethyl-1,3-dihydro-1-oxo-isoindole

Prepared from2-[N-methyl-N-((pyridin-3-yl)-methyl)-3-amino-propyl]-5,6-dimethyl-phthalimideanalogously to Example 3.

Yield: 73% of theory, Melting point: 93°-95° C.; Calculated: C, 74.27;H, 7.79; N, 12.99. Found: C, 74.27; H, 7.73; N, 12.92.

EXAMPLE 302-[N-Methyl-N-((pyridin-3-yl)-methyl)-3-amino-propyl]-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinolinehydrochloride

Prepared from2-(2-formyl-ethyl)-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinolineand 3-(methylamino-methyl)-pyridine analogously to Example 4.

Yield: 83% of theory, Melting point: 203°-205° C.; Calculated: C, 61.61;H, 6.20; N, 10.79; Cl, 9.09. Found: C, 61.72; H, 6.18; N, 10.62; Cl,8.96.

EXAMPLE 312-[N-Methyl-N-((pyridin-3-yl)-methyl)-3-amino-propyl]-5,6-dimethyl-phthalimide

Prepared from 2-(2-formyl-ethyl)-5,6-dimethyl-phthalimide and3-(methylamino-methyl)-pyridine analogously to Example 4.

Yield: 80% of theory, Melting point: 71°-72° C.; Calculated: C, 71.19;H, 6.87; N, 12.45. Found: C, 70.98; H, 6.77; N, 12.32.

EXAMPLE 322-[N-Methyl-N-(3-(pyridin-4-yl)-propyl)-3-amino-propyl]-5,6-dimethyl-phthalimidedihydrochloride-hemihydrate

Prepared from 2-(2-formyl-ethyl)-5,6-dimethyl-phthalimide and4-(3-methylamino-propyl)-pyridine analogously to Example 4.

Yield: 68% of theory, Calculated: C, 59.05; H, 6.76; N, 9.39; Cl, 15.84.Found: C, 58.95; H, 6.86; N, 9.11; Cl, 15.64. R_(f) value: 0.60 (silicagel, ethyl acetate/ethanol/ammonia=90/10/1).

EXAMPLE 332-[N-Methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-ethyl)-3-amino-propyl]-5,6-dimethyl-phthalimide

Prepared from 2-(2-formyl-ethyl)-5,6-dimethyl-phthalimide and4-(2-methylamino-ethyl)-6,7-dimethoxy-isoquinoline analogously toExample 4.

Yield: 76% of theory, Melting point: 122°-124° C.; Calculated: C, 70.26;H, 6.77; N, 9.10. Found: C, 70.43; H, 6.85; N, 8.98.

EXAMPLE 342-[N-Methyl-N-(2-(pyridin-2-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-phthalimide

Prepared from 2-(2-formyl-ethyl)-5,6-dimethoxy-phthalimide and2-(2-methylamino-ethyl)-pyridine analogously to Example 4.

Yield: 63% of theory, Melting point: 120°-122° C.; Calculated: C, 65.78;H, 6.58; N, 10.96. Found: C, 65.90; H, 6.55; N, 11.11.

EXAMPLE 352-[N-Methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-phthalimidehemihydrate

Prepared from 2-(2-formyl-ethyl)-5,6-dimethoxy-phthalimide and4-(2-methylamino-ethyl)-6,7-dimethoxy-isoquinoline analogously toExample 4.

Yield: 75% of theory, Melting point: 158°-160° C.; Calculated: C, 64.52;H, 6.42; N, 8.36. Found: C, 64.44; H, 6.46; N, 8.44.

EXAMPLE 362-[N-Methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-ethyl)-3-amino-propyl]-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinolinedihydrochloride-hemihydrate

Prepared from2-(2-formyl-ethyl)-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinolineand 4-(2-methylamino-ethyl)-6,7-dimethoxy-isoquinoline analogously toExample 4.

Yield: 77% of theory, Calculated: C, 57.96; H, 6.12; N, 7.51; Cl, 12.67.Found: C, 57.85; H, 6.06; N, 7.34; Cl, 12.82. R_(f) value: 0.25 (silicagel, ethyl acetate/ethanol/ammonia=80/40/2).

EXAMPLE 372-[N-Methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-ethyl)-3-amino-propyl]-6,7-methylenedioxy-1,2,3,4-tetrahydro-isoquinolinetrihydrochloride-dihydrate

Prepared from2-[N-methyl-N-(2-(6,7-dimethoxy-isoquinolin-4-yl)-ethyl)-3-amino-propyl]-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinolineanalogously to Example 5.

Yield: 83% of theory, Calculated: C, 53.24; H, 6.62; N, 6.90; Cl, 17.46.Found: C, 53.06; H, 6.66; N, 6.91; Cl, 17.53. R_(f) value: 0.15 (silicagel, methylene chloride/ethanol=4/1).

EXAMPLE 382-[N-Methyl-N-(3-(pyridin-4-yl)-propyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-isoindoledihydrochloride-monohydrate

Prepared from2-[N-methyl-N-(3-(pyridin-4-yl)-propyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindoleanalogously to Example 5.

Yield: 55% of theory, Melting point: 248°-250° C.; Calculated: C, 57.38;H, 7.66; N, 9.12; Cl, 15.40. Found: C, 57.28; H, 7.52; N, 9.02; Cl,15.50.

EXAMPLE 392-[N-Methyl-N-(4-(thien-2-yl)-butyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindolehydrochloride

Prepared from2-[N-methyl-N-(4-(thien-2-yl)-butyl)-3-amino-propyl]-5,6-dimethoxy-phthalimideanalogously to Example 3.

Yield: 30% of theory, Melting point: 171°-172° C. (decomp.); Calculated:C, 60.19; H, 7.12; N, 6.38; Cl, 8.08; S, 7.30. Found: C, 59.92; H, 7.21;N, 6.44; Cl, 8.29; S, 7.41.

EXAMPLE 402-[N-Methyl-N-(4-(thien-2-yl)-butyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolinehydrochloride

0.83 g (4.0 mmol) of 6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolineare dissolved in 15 ml of dimethylformamide and 0.49 g (4.4 mmol) ofpotassium tert.butoxide are added with stirring. After the exothermicreaction has died away the potassium salt is precipitated. It is cooledto 0° C., 1.3 g (4.4 mmol) ofN-methyl-N-(4-(thien-2-yl)-butyl)-3-amino-1-bromo-propane are added andthe mixture is left to react at 0° C. for 4 hours. After decompositionwith ice water, the mixture is extracted with ethyl acetate, the organicphase is washed with water, dried over magnesium sulphate, concentratedby evaporation and purified over a silica gel column. The free base thusobtained is dissolved in acetone and the hydrochloride is precipitatedwith ethereal hydrochloric acid.

Yield: 0.63 g (35% of theory), Melting point: 116°-119° C. (decomp.);Calculated: C, 60.98; H, 7.34; N, 6.18; Cl, 7.83; S, 7.08. Found: C,61.15; H, 7.38; N, 6.08; Cl, 7.68; S, 6.97.

EXAMPLE 412-[N-Methyl-N-(2-(benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1-thioxo-1,2,3,4-tetrahydro-isoquinoline

1.7 g (3.9 mmol) of2-[N-methyl-N-(2-(benzo[b]thien-3-yl)-ethyl)-3-amino-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinolineand 0.57 g (2.0 mmol) of2,4-bis-(methylthio)-1,3-dithia-2,4-diphosphetan-2,4-disulphide aresuspended in 15 ml of toluene and refluxed for 2 hours. The mixture isthen evaporated down in vacuo and purified over a silica gel column withmethylene chloride and increasing amounts of methanol.

Yield: 0.99 g (56% of theory), Calculated: C, 66.06; H, 6.65; N, 6.16;S, 14.08. Found: C, 65.85; H, 6.58; N, 6.28; S, 14.26. R_(f) value: 0.49(silica gel, methylene chloride).

EXAMPLE I Tablets containing 25 mg of2-[N-methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindolehydrochloride

    ______________________________________                                        Composition:                                                                  1 tablet contains:                                                            ______________________________________                                        Active substance       25.0 mg                                                Corn starch            57.0 mg                                                Lactose                48.0 mg                                                Polyvinylpyrrolidone   4.0 mg                                                 Magnesium stearate     1.0 mg                                                                        135.0 mg                                               ______________________________________                                    

METHOD OF PREPARATION

The active substance, corn starch, lactose and polyvinylpyrrolidone weremixed together and moistened with water. The moist mixture is pushedthrough a screen with a mesh size of 1.5 mm and dried at about 45° C.The dry granulate is passed through a 1.0 mm mesh screen and mixed withmagnesium stearate. The final mixture is compressed in a tablet presswith dies 7 mm in diameter provided with a dividing notch to formtablets.

Weight of tablet: 135 mg.

EXAMPLE II Coated tablets containing 20 mg of2-[N-methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindolehydrochloride

    ______________________________________                                         1 tablet core contains:                                                      ______________________________________                                        Active substance       20.0 mg                                                Corn starch            41.5 mg                                                Lactose                30.0 mg                                                Polyvinylpyrrolidone   3.0 mg                                                 Magnesium stearate     0.5 mg                                                                        95.0 mg                                                ______________________________________                                    

METHOD OF PREPARATION

The active substance, corn starch, lactose and polyvinylpyrrolidone arethroughly mixed and moistened with water. The moist mass is forcedthrough a 1 mm screen, dried at about 45° C. and then the granulate ispassed through the same screen. After magnesium stearate has been added,convex tablet cores with a diameter of 6 mm are compressed in a tabletmaking machine. The tablet cores thus produced are coated in knownmanner with a coating consisting essentially of sugar and talc. Thefinished coated tablets are polished with wax.

Weight of coated tablet: 145 mg.

EXAMPLE III Ampoules containing 50 mg of2-[N-methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindolehydrochloride

    ______________________________________                                         1 ampoule contains:                                                          ______________________________________                                        Active substance       50.0   mg                                              Sorbitol               30.0   mg                                              Water for injections ad                                                                              2.0    ml                                              ______________________________________                                    

METHOD OF PREPARATION

In a suitable mixing vessel the active substance is dissolved in waterfor injections and the solution is made isotonic with sorbitol. Afterbeing filtered through a diaphragm filter the solution is transferredunder a current of N₂ into purified and sterilized ampoules andautoclaved for 20 minutes in a jet of steam.

EXAMPLE IV Suppositories containing 30 mg of2-[N-methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindolehydrochloride

    ______________________________________                                         1 suppository contains:                                                      ______________________________________                                        Active substance          0.030   g                                           Hard fat (e.g. Witepsol H 19 and W 45)                                                                  1.670   g                                                                     1.700   g                                           ______________________________________                                    

METHOD OF PREPARATION

The hard fat is melted. At 38° C. the ground active substance ishomogeneously dispersed in the melt. It is cooled to 35° C. and pouredinto slightly chilled suppository moulds.

EXAMPLE V Drops solution containing 20 mg of2-[N-methyl-N-(2-(thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindolehydrochloride

    ______________________________________                                         100 ml of solution contain:                                                  ______________________________________                                        Active substance       0.4      g                                             Hydroxyethylcellulose  0.15     g                                             Tartaric acid          0.1      g                                             Sorbitol solution with 70% dry matter                                                                30.0     g                                             Glycerol               10.0     g                                             Benzoic acid           0.15     g                                             Dist. water ad         100      ml                                            ______________________________________                                    

METHOD OF PREPARATION

The distilled water is heated to 70° C. The hydroxyethylcellulose,benzoic acid and tartaric acid are dissolved therein with stirring. Themixture is cooled to ambient temperature and the glycerol and sorbitolsolution are added with stirring. At ambient temperature the activesubstance is added and stirred until completely dissolved. The syrup isthen evacuated of any air with stirring.

What is claimed is:
 1. A heteroaromatic amine derivative of formula##STR14## wherein A is a carbonyl or thiocarbonyl group;B is a methylenegroup; E is a straight-chained C₂ -C₄ alkylene group, which can besubstituted by a C₁ -C₃ alkyl group; G is a straight-chained C₁ -C₆alkylene group; which can be substituted by a C₁ -C₃ alkyl group; R₁ andR₂, which may be identical or different, are hydrogen atoms, C₁ -C₃alkyl or C₁ -C₃ alkoxy groups; R₃ is a hydrogen atom, a C₃ -C₅ alkenylgroup, an alkyl or phenylalkyl group, wherein the alkyl moiety maycontain from 1 to 3 carbon atoms; n is 0 and Het is a benzo[b]thienylgroup, whilst the carbon structure of the above-mentioned homocyclic orheteroaromatic ring may be mono- or disubstituted by a halogen atom orby an alkyl, hydroxy, alkoxy, phenylalkoxy, phenyl, dimethoxyphenyl,nitro, amino, acetylamino, carbamoylamino, N-alkyl-carbamoylamino,hydroxymethyl, mercapto, alkylmercapto, alkylsulphinyl, alkylsulphonyl,alkylsulphonyloxy, alkylsulphonylamino, alkoxycarbonylmethoxy,carboxymethoxy or alkoxymethyl group or may be substituted by amethylenedioxy or ethylenedioxy group, whereby the above-mentioned alkylmoieties may each contain from 1 to 3 carbon atoms; or n is 0 or 1, andHet is a thienyl group, whilst the carbon structure of theabove-mentioned heteroaromatic ring may be mono- or disubstituted by ahalogen atom or by an alkyl, hydroxy, alkoxy, phenylalkoxy, phenyl,dimethoxyphenyl, nitro, amino, acetylamino, carbamoylamino,N-alkyl-carbamoylamino, hydroxymethyl, mercapto, alkylmercapto,alkylsulphinyl, alkylsulphonyl, alkylsulphonyloxy, alkylsulphonylamino,alkyoxycarbonylmethoxy, carboxymethoxy or alkoxymethyl group or may besubstituted by a methylenedioxy or ethylenedioxy group, whereby theabove-mentioned alkyl moieties may each contain from 1 to 3 carbonatoms;and the N-oxide, the enantiomer, diastereomer or acid additionsalt thereof.
 2. The physiologically acceptable acid addition salt ofthe compound as recited in claim
 1. 3. A heteroaromatic amine derivativeof formula ##STR15## wherein A is a carbonyl or thiocarbonyl group;B isa methylene group; E is an n-propylene group; G is a methylene,ethylene, n-propylene, n-butylene or n-pentylene group; R₁ and R₂, whichmay be identical or different, are hydrogen atoms, methyl or methoxygroups; R₃ is a hydrogen atom, a methyl or allyl group; n is 0, and Hetis a benzo[b]thien-2-yl, benzo[b]thien-3-yl,6-hydroxybenzo[b]thien-3-yl, 6-methoxy-benzo[b]thien-3-yl,5,6-dimethoxy-benzo[b]thien-3-yl, 2,5-dimethyl-benzo[b]thien-3-yl,5-methoxy-benzo[b]thien-2-yl, 6-methoxy-benzo[b]thien-2-yl,6-methylmercapto-benzo[b]thien-3-yl,6-methylsulphinyl-benzo-[b]thien-3-yl,6-methylsulphonyl-benzo[b]thien-3-yl,6-methylsulphonyloxy-benzo[b]thien-3-yl,6-ethoxycarbonylmethoxy-benzo[b]thien-3-yl,6-carboxymethoxy-benzo[b]thien-3-yl, 6-dimethylamino-benzo[b]thien-3-yl,6-methylsulphonylamino-benzo[b]thien-3-yl,6-acetamino-benzo[b]thien-3-yl or benzo[b]-thien-4-yl group; or n is 0or 1, and Het is a thien-2-yl, thien-3-yl, 5-methyl-thien-2-yl,2-methyl-thien-3-yl, 3-methyl-thien-2-yl or 2,5-dimethyl-thien-3-ylgroup;the enantiomer, diastereomer or acid addition salt thereof.
 4. Theheteroaromatic amine derivative as recited in claim 3 whereinR₁ and R₂,which may be identical or different, are methyl or methoxy groups; R₃ isa hydrogen atom or a methyl group; n is 0, and Het is abenzo[b]thien-2-yl or benzo[b]thien-3-yl group; or n is 0 or 1, and Hetis a thien-2-yl or thien-3-yl group;the enantiomer, diastereomer or acidaddition salt thereof.
 5. The physiologically acceptable acid additionsalt of the compound as recited in claim
 3. 6. The physiologicallyacceptable acid addition salt of the compound as recited in claim
 4. 7.2-[N-Methyl-N-(2-thien-3-yl)-ethyl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindoleor the acid addition salt thereof.
 8. The physiologically acceptableacid addition salt of the compound as recited in claim
 7. 9.2-[N-Methyl-N-(2-benzo[b]thien-3-yl)-3-amino-propyl]-5,6-dimethoxy-1,3-dihydro-1-oxo-isoindoleor the acid addition salt thereof.
 10. The physiologically acceptableacid addition salt of the compound as recited in claim 9.